WO2020107820A1 - Préparation d'injection de cavité articulaire et utilisation associée - Google Patents

Préparation d'injection de cavité articulaire et utilisation associée Download PDF

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Publication number
WO2020107820A1
WO2020107820A1 PCT/CN2019/087849 CN2019087849W WO2020107820A1 WO 2020107820 A1 WO2020107820 A1 WO 2020107820A1 CN 2019087849 W CN2019087849 W CN 2019087849W WO 2020107820 A1 WO2020107820 A1 WO 2020107820A1
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WO
WIPO (PCT)
Prior art keywords
xanthan gum
preparation
million
joint cavity
deacetylated
Prior art date
Application number
PCT/CN2019/087849
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English (en)
Chinese (zh)
Inventor
凌沛学
刘飞
邵华荣
陈磊
张治云
张晓元
陈启鑫
韩冠英
程艳玲
张建强
张岱州
Original Assignee
山东省药学科学院
山东福瑞达医药集团有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 山东省药学科学院, 山东福瑞达医药集团有限公司 filed Critical 山东省药学科学院
Priority to US17/297,467 priority Critical patent/US11376274B2/en
Publication of WO2020107820A1 publication Critical patent/WO2020107820A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/723—Xanthans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
    • A61K31/728—Hyaluronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/737—Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
    • C08B37/0033—Xanthan, i.e. D-glucose, D-mannose and D-glucuronic acid units, saubstituted with acetate and pyruvate, with a main chain of (beta-1,4)-D-glucose units; Derivatives thereof

Definitions

  • the invention relates to the technical field of orthopaedic medicine, in particular to a joint cavity injection preparation and its application.
  • Osteoarthritis is a common degenerative joint disease characterized by the destruction of articular cartilage and bone hyperplasia, and the incidence is higher in the elderly. With the aging population in my country and the increase in the number of obese people, the incidence of OA continues to rise. In OA lesions, the viscoelasticity of joint synovial fluid is significantly reduced, and cartilage is degraded and destroyed, resulting in joint dysfunction.
  • Viscoelastic supplementation is one of the main methods of clinical treatment of OA.
  • HA hyaluronic acid
  • the lubrication and buffering function of joint synovial fluid can be restored, and cartilage tissue repair can be promoted.
  • HA is easily degraded by hyaluronidase and free radicals in the body, and stays in the joint cavity for a short time, therefore, the development of new viscoelastic supplements with similar viscoelasticity and better stability for OA treatment can reduce drug administration It is of great significance to avoid infections caused by repeated injections and improve patient compliance.
  • Xanthan gum is a biopolymer polysaccharide, similar to HA, with better viscoelasticity and better stability.
  • XG is a water-soluble extracellular polysaccharide produced by fermenting Xanthomonas camperstris with black sugar as the main raw material.
  • the relative molecular mass (Mr) of XG is 2 ⁇ 10 6-2 ⁇ 10 7.
  • the basic structure of the XG molecule is composed of pentose repeating units, the main chain is D-glucose connected by ⁇ -1,4 bonds, and the side chain is a trisaccharide formed by alternately connecting D-mannose and D-glucuronic acid.
  • the mannose connected to the main chain is partially acetylated at the 6-position C, and the mannose at the end of some side chains is connected to a pyruvate group at the 6-position C;
  • the secondary structure is that the trisaccharide side chain is wound around the main chain in reverse, through hydrogen The bond maintains a double helix or multi-helix structure;
  • the tertiary structure is a secondary helix structure composed of a network structure through non-covalent bonds.
  • the structure and conformation of xanthan gum determine the functional characteristics of its solution: the complex aggregation structure and intermolecular force of xanthan gum determine its high viscosity at low shear and low concentration, which is more than other polysaccharide solutions.
  • the removal of acetyl groups and the removal of pyruvate groups of xanthan gum will significantly change the properties of xanthan gum.
  • the intermolecular force of xanthan gum after the pyruvate group is removed is significantly reduced, and the pyruvate group may form hydrogen bonds with each other in the xanthan gum molecule and interact with the acetyl of the adjacent side chain.
  • the base generates hydrogen bonds to stabilize the molecular structure of xanthan gum.
  • the acetyl group is usually considered to provide the intramolecular interaction force, so the xanthan gum molecule becomes more compliant after the acetyl group is removed.
  • the XG solution has specific rheological properties, especially the characteristics and viscoelasticity of non-Newtonian fluids: when the joint is at a low impact frequency, it is a viscous solution that acts on the synovial tissue, various tissue planes, ligaments and collagen structures in the joint. Lubrication function reduces friction between tissues. When the joint is at a high impact frequency, the viscous feature is converted to an elastic feature to cushion the impact of stress on the joint.
  • XG can form a macromolecular network in joint synovial fluid, regulate the diffusion of water and macromolecular substances, act as a diffusion barrier in the joint, and act as a barrier to bacteria, toxins, immune complexes, etc., protecting cartilage and synovium Protected from enzymes, chemicals and toxins, it stabilizes cell membranes and inactivates the sensitivity of cell membrane receptors.
  • xanthan gum preparations can perform long-term treatment of OA.
  • Patent application 2017100752628 discloses a pharmaceutical preparation containing low molecular weight xanthan gum for joint cavity injection and a preparation method thereof, and mentions that a pharmaceutical preparation containing a low molecular weight xanthan gum with a relative molecular weight of 100,000 to 1.99 million can be used to prevent rheumatism and Rheumatoid arthritis, osteoarthritis, the protection of articular cartilage in osteoarthritis and the repair of damaged articular cartilage, mainly solve the conventional molecular weight of xanthan gum (relative molecular weight of 2-20 million) due to stability is not easy to be enzymes in the body And the problem of free radical degradation and difficult to be eliminated by the body's metabolism.
  • the low molecular weight xanthan gum drug preparation is used in the treatment of osteoarthritis. Due to the stable structure, it enters the visceral tissue through the blood circulation after joint cavity injection. Dose injection is easy to cause the disadvantages of increased spleen weight and monocyte number, poor biocompatibility, which seriously affects its use effect and hinders further use; while using deacetylated xanthan gum of equivalent molecular weight, even the molecular weight and concentration are more The high deacetylated xanthan gum can solve the above problems while ensuring excellent therapeutic effect.
  • the invention provides a joint cavity injection preparation and its application. It uses deacetylated xanthan gum for the treatment of osteoarthritis. It has excellent therapeutic effect and eliminates the adverse reactions caused by the long-term repeated injection of high-dose xanthan gum. It has excellent biocompatibility, a higher safe dosage range, and safer use, which solves the problems in the existing technology.
  • the present invention provides a joint cavity injection preparation whose active ingredient is deacetylated xanthan gum.
  • the mass percentage of the deacetylated xanthan gum to the volume of the joint cavity injection preparation is 0.01%-10% (w/v), preferably 0.5%-8% (w/v), more preferably 1%-5% (w /v).
  • the molecular weight of the deacetylated xanthan gum is 100,000 to 20 million, preferably 500,000 to 10 million, and more preferably 800 to 3 million.
  • the preparation also includes one or more of sodium hyaluronate, chondroitin sulfate, chitosan or trehalose.
  • the preparation also includes disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium chloride and water for injection.
  • the formulation includes the following components by mass volume fraction: deacetylated xanthan gum 1%-5%, disodium hydrogen phosphate 0.4%-0.7%, sodium dihydrogen phosphate 0.1%-0.16%, sodium chloride 0.25%- 0.41%, the balance of water for injection.
  • the pH of the preparation is 5.5-9, and the osmotic pressure is 200-400 mOsmol/L.
  • the present invention also provides the use of deacetylated xanthan gum in the preparation of a medicament for treating osteoarthritis.
  • the biological safety of the medicine for treating osteoarthritis prepared by deacetylated xanthan gum is higher than that of the medicine for treating osteoarthritis prepared by xanthan gum.
  • the biological safety of drugs prepared with deacetylated xanthan gum is superior to xanthan gum.
  • the biosafety of the former is significantly better than that of the latter.
  • the deacetylated xanthan gum and xanthan gum when the dosage is the same (5%), the biological safety of deacetylated xanthan gum is significantly higher than that of xanthan gum.
  • the dosage of the deacetylated xanthan gum in the medicine is 0.01%-10% (w/v), preferably 0.5%-8% (w/v), more preferably 1%-5% (w/v);
  • the molecular weight of the deacetylated xanthan gum is 100,000 to 20 million, preferably 500,000 to 10 million, and more preferably 800 to 3 million.
  • the dosage form of the medicine is selected from injection preparations, gels, ointments, aerosols or sprays.
  • the invention also provides a method for preparing a joint cavity injection preparation, comprising the step of using deacetylated xanthan gum as the active ingredient of the injection preparation.
  • the deacetylated xanthan gum in the present invention may be commercially available deacetylated xanthan gum, or may be prepared by the following preparation method:
  • the preparation step of the deacetylated xanthan gum also includes the step of drying the precipitate of step (3).
  • the pH of the joint cavity preparation prepared by the above method is 5.5-9, and the osmotic pressure is 200-400 mOsmol/L.
  • the present invention uses deacetylated xanthan gum with different conformation and physicochemical properties from xanthan gum instead of xanthan gum, and is used for the production of drugs and preparations for osteoarthritis. Better biocompatibility and safety. Compared with xanthan gum, deacetylated xanthan gum is used in the production of drugs and preparations for osteoarthritis when the molecular weight or molecular weight and concentration are higher. It can also be a good solution for the slow elimination of xanthan gum in the body The resulting problem of poor biocompatibility provides a new way for the development of new drugs such as osteoarthritis drugs and joint cavity injection preparations.
  • the Mw of the deacetylated xanthan gum was detected by multi-angle laser to be 1 million.
  • the hydroxylamine hydrochloride colorimetric method showed that the structure did not contain acetyl groups.
  • the Mw of the deacetylated xanthan gum was detected by multi-angle laser to be 2 million.
  • the hydroxylamine hydrochloride colorimetric method showed that the structure did not contain acetyl groups.
  • the Mw of the deacetylated xanthan gum was detected by multi-angle laser to be 4 million.
  • the hydroxylamine hydrochloride colorimetric method showed that the structure did not contain acetyl groups.
  • the Mw of the deacetylated xanthan gum was detected by multi-angle laser to be 5 million.
  • the hydroxylamine hydrochloride colorimetric method showed that the structure did not contain acetyl groups.
  • the Mw of the deacetylated xanthan gum detected by multi-angle laser was 2.6 million.
  • the hydroxylamine hydrochloride colorimetric method showed that the structure did not contain acetyl groups.
  • deacetylated xanthan gum prepared by the above method is used for the preparation of joint cavity injections:
  • a total of 64 New Zealand white rabbits were randomly divided into 8 groups, 8 in each group, half male and female: normal control group, negative control group (physiological saline), and 1 group of deacetylated xanthan gum (Example 6, 1%) , 1 million), deacetylated xanthan gum 2 groups (Example 7, 3%, 1 million), deacetylated xanthan gum 3 groups (Example 8,5%, 1 million), deacetylated xanthan gum 4 groups (Example 9, 1%, 5 million), ordinary xanthan gum group (1%, 1 million), sodium hyaluronate control group.
  • the knee osteoarthritis model was established by cutting the left knee ligament through anterior cruciate ligament excision. After successful modeling, the corresponding drugs or saline were injected into the joint cavity respectively, and the dosage was 0.3 mL/joint.
  • the sodium hyaluronate control group was administered once a week for a total of 5 times.
  • the deacetylated xanthan gum group and the common xanthan gum group were administered once every 5 weeks for a total of 2 times. Animals in each group They were sacrificed 10 weeks after the first administration. Pathological observation of articular cartilage was performed and scored. The score results are shown in Table 1.
  • a special bovine bone steel knife was used to strip the cartilage of the articular cartilage to make a cartilage block with a uniform thickness (1.89mm).
  • the reciprocating friction tester was used to detect the tribological index under the lubrication of different injections, including the dry friction group, saline group, and glass acid.
  • deacetylated xanthan gum 1 group (Example 6, 1%, 1 million), deacetylated xanthan gum 2 groups (Example 7, 3%, 1 million), deacetylated xanthan gum 3 groups (implemented Example 8, 5%, 1 million), deacetylated xanthan gum 4 groups (Example 9, 1%, 5 million), ordinary xanthan gum group (1%, 1 million), sodium hyaluronate control group.
  • Test machine setting parameters test force is 3N, reciprocating frequency is 1Hz. The test results are shown in Table 2 below.
  • Eighty SD rats were randomly divided into 8 groups, 10 in each group, half male and female: negative control group (physiological saline), deacetylated xanthan gum group 1 (Example 6, 1%, 1 million), deacetylated Xanthan gum 2 groups (Example 7, 3%, 1 million), deacetylated xanthan gum 3 groups (Example 8, 5%, 1 million), deacetylated xanthan gum 4 groups (Example 9, 1% , 5 million), deacetylated xanthan gum 5 groups (Example 10, 5%, 5 million), ordinary xanthan gum 1 group (5%, 1 million), ordinary xanthan gum 2 groups (5%, 5 million) ), and the corresponding drugs or physiological saline were injected into the joint cavity respectively, the dosage was 0.06 mL/joint, and the drug was administered once every 2 weeks for 6 consecutive months. Two weeks after the last administration, the anesthetized animal was bled for routine blood examination. After

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  • Chemical & Material Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Epidemiology (AREA)
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  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Emergency Medicine (AREA)
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Abstract

L'invention concerne une préparation d'injection de cavité articulaire et son utilisation. La préparation d'injection de cavité articulaire utilise de la gomme xanthane désacétylée, et présente une meilleure biocompatibilité et une plage posologique plus sûre par comparaison avec des préparations d'injection de cavité articulaire de gomme xanthane existantes.
PCT/CN2019/087849 2018-11-30 2019-05-21 Préparation d'injection de cavité articulaire et utilisation associée WO2020107820A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US17/297,467 US11376274B2 (en) 2018-11-30 2019-05-21 Joint cavity injection preparation and use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811455378.5A CN109260219B (zh) 2018-11-30 2018-11-30 一种关节腔注射制剂及其应用
CN201811455378.5 2018-11-30

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WO2020107820A1 true WO2020107820A1 (fr) 2020-06-04

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CN (1) CN109260219B (fr)
WO (1) WO2020107820A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN109260219B (zh) 2018-11-30 2021-03-09 山东省药学科学院 一种关节腔注射制剂及其应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101940587A (zh) * 2009-07-03 2011-01-12 山东省生物药物研究院 一种含有黄原胶的关节腔内注射用药物制剂
CN102946855A (zh) * 2010-06-23 2013-02-27 爱尔康研究有限公司 含有妥布霉素和***的局部用眼科混悬剂
CN105251048A (zh) * 2015-10-16 2016-01-20 山东福瑞达医药集团公司 一种含黄原胶的可注射型软骨组织保护及修复材料
CN106692179A (zh) * 2017-02-13 2017-05-24 山东省药学科学院 关节腔注射用含低分子量黄原胶的药物制剂及其制备方法
CN109260219A (zh) * 2018-11-30 2019-01-25 山东省药学科学院 一种关节腔注射制剂及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8623839B2 (en) * 2011-06-30 2014-01-07 Depuy Mitek, Llc Compositions and methods for stabilized polysaccharide formulations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101940587A (zh) * 2009-07-03 2011-01-12 山东省生物药物研究院 一种含有黄原胶的关节腔内注射用药物制剂
CN102946855A (zh) * 2010-06-23 2013-02-27 爱尔康研究有限公司 含有妥布霉素和***的局部用眼科混悬剂
CN105251048A (zh) * 2015-10-16 2016-01-20 山东福瑞达医药集团公司 一种含黄原胶的可注射型软骨组织保护及修复材料
CN106692179A (zh) * 2017-02-13 2017-05-24 山东省药学科学院 关节腔注射用含低分子量黄原胶的药物制剂及其制备方法
CN109260219A (zh) * 2018-11-30 2019-01-25 山东省药学科学院 一种关节腔注射制剂及其应用

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US20210353662A1 (en) 2021-11-18
US11376274B2 (en) 2022-07-05
CN109260219B (zh) 2021-03-09

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